Malik, V. S. & Hu, F. B. The role of sugar-sweetened beverages in the global epidemics of obesity and chronic diseases. Nat. Rev. Endocrinol. 18, 205–218 (2022).
World Health Organization. Guideline: sugars intake for adults and children. WHO https://www.who.int/publications/i/item/9789241549028 (2015).
Yang, Q. et al. Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern. Med. 174, 516–524 (2014).
Russell, C., Baker, P., Grimes, C., Lindberg, R. & Lawrence, M. A. Global trends in added sugars and non-nutritive sweetener use in the packaged food supply: drivers and implications for public health. Public Health Nutr. 26, 952–964 (2023).
Magkos, F. et al. On the pathogenesis of obesity: causal models and missing pieces of the puzzle. Nat. Metab. 6, 1856–1865 (2024).
Herman, M. A. & Birnbaum, M. J. Molecular aspects of fructose metabolism and metabolic disease. Cell Metab. 33, 2329–2354 (2021).
Woods, H. F. & Krebs, H. A. Lactate production in the perfused rat liver. Biochem. J. 125, 129–139 (1971).
Johnson, R. J. et al. The fructose survival hypothesis for obesity. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 378, 20220230 (2023).
Diggle, C. P. et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J. Histochem. Cytochem. 57, 763–774 (2009).
Li, Y. et al. Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction. Exp. Mol. Med. 55, 2417–2432 (2023).
Helsley, R. N. et al. Tissue-specific fructose metabolism in obesity and diabetes. Curr. Diab. Rep. 20, 64 (2020).
Maenpaa, P. H., Raivio, K. O. & Kekomaki, M. P. Liver adenine nucleotides: fructose-induced depletion and its effect on protein synthesis. Science 161, 1253–1254 (1968).
van den Berghe, G., Bronfman, M., Vanneste, R. & Hers, H. G. The mechanism of adenosine triphosphate depletion in the liver after a load of fructose. A kinetic study of liver adenylate deaminase. Biochem. J. 162, 601–609 (1977).
Bawden, S. J. et al. Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: a (31)P MRS study. Clin. Nutr. 35, 645–649 (2016).
Abdelmalek, M. F. et al. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology 56, 952–960 (2012).
Bode, J. C., Zelder, O., Rumpelt, H. J. & Wittkamp, U. Depletion of liver adenosine phosphates and metabolic effects of intravenous infusion of fructose or sorbitol in man and in the rat. Eur. J. Clin. Invest. 3, 436–441 (1973).
Samarah, L. Z. et al. Spatial metabolic gradients in the liver and small intestine. Nature 648, 182–190 (2025).
Van den Berghe, G. Fructose: metabolism and short-term effects on carbohydrate and purine metabolic pathways. Prog. Biochem. Pharmacol. 21, 1–32 (1986).
Petrie, J. L. et al. The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. Am. J. Physiol. Endocrinol. Metab. 305, E1255–E1265 (2013).
Cox, C. L. et al. Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans. Nutr. Metab. 9, 68 (2012).
Zhang, P. et al. Dietary intake of fructose increases purine de novo synthesis: a crucial mechanism for hyperuricemia. Front. Nutr. 9, 1045805 (2022).
Evans, P. R., Farrants, G. W. & Hudson, P. J. Phosphofructokinase: structure and control. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 293, 53–62 (1981).
Sun, S. Z. & Empie, M. W. Fructose metabolism in humans - what isotopic tracer studies tell us. Nutr. Metab. 9, 89 (2012).
Woods, H. F., Eggleston, L. V. & Krebs, H. A. The cause of hepatic accumulation of fructose 1-phosphate on fructose loading. Biochem. J. 119, 501–510 (1970).
Topping, D. L. & Mayes, P. A. Comparative effects of fructose and glucose on the lipid and carbohydrate metabolism of perfused rat liver. Br. J. Nutr. 36, 113–126 (1976).
Delannoy, P. et al. Aldose reductase, fructose and fat production in the liver. Biochem J. 482, 295–307 (2025).
Liu, L. et al. Triose kinase controls the lipogenic potential of fructose and dietary tolerance. Cell Metab. 32, 605–618 (2020).
Kim, M. et al. Intestinal, but not hepatic, ChREBP is required for fructose tolerance. JCI Insight 2, e96703 (2017).
Kim, M. S. et al. ChREBP regulates fructose-induced glucose production independently of insulin signaling. J. Clin. Invest. 126, 4372–4386 (2016).
An, J. et al. Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism. Cell Rep. 44, 115278 (2025).
Kabashima, T., Kawaguchi, T., Wadzinski, B. E. & Uyeda, K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc. Natl Acad. Sci. USA 100, 5107–5112 (2003).
Lanaspa, M. A. et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS ONE 7, e47948 (2012).
Softic, S. et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J. Clin. Invest. 127, 4059–4074 (2017).
Beysen, C. et al. Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans. Am. J. Physiol. Endocrinol. Metab. 315, E126–E132 (2018).
Stanhope, K. L. et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Invest. 119, 1322–1334 (2009).
Taskinen, M. R. et al. Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity. J. Intern. Med. 282, 187–201 (2017).
Cox, C. L. et al. Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women. Eur. J. Clin. Nutr. 66, 201–208 (2012).
Chong, M. F., Fielding, B. A. & Frayn, K. N. Mechanisms for the acute effect of fructose on postprandial lipemia. Am. J. Clin. Nutr. 85, 1511–1520 (2007).
Softic, S. et al. Dietary sugars alter hepatic fatty acid oxidation via transcriptional and post-translational modifications of mitochondrial proteins. Cell Metab. 30, 735–753 (2019).
Lanaspa, M. A. et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J. Biol. Chem. 287, 40732–40744 (2012).
Zhao, S. et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579, 586–591 (2020).
Tharabenjasin, P. et al. Acute interactions between intestinal sugar and calcium transport in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G1–G12 (2014).
Johnson, R. J. et al. Fructokinase, fructans, intestinal permeability, and metabolic syndrome: an equine connection? J. Equine Vet. Sci. 33, 120–126 (2013).
Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020).
Bergheim, I. et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J. Hepatol. 48, 983–992 (2008).
Stanhope, K. L. et al. Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women. J. Clin. Endocrinol. Metab. 96, E1596–E1605 (2011).
Fowle-Grider, R. et al. Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer. Nature 636, 737–744 (2024).
Taylor, S. R. et al. Dietary fructose improves intestinal cell survival and nutrient absorption. Nature 597, 263–267 (2021).
Hirano, T., Mamo, J., Poapst, M. & Steiner, G. Very-low-density lipoprotein triglyceride kinetics in acute and chronic carbohydrate-fed rats. Am. J. Physiol. 255, E236–E240 (1988).
Hieronimus, B. & Stanhope, K. L. Dietary fructose and dyslipidemia: new mechanisms involving apolipoprotein CIII. Curr. Opin. Lipidol. 31, 20–26 (2020).
Crescenzo, R. et al. Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Eur. J. Nutr. 52, 537–545 (2013).
Hieronimus, B. et al. Effects of consuming beverages sweetened with fructose, glucose, high-fructose corn syrup, sucrose, or aspartame on OGTT-derived indices of insulin sensitivity in young adults. Nutrients 16, 151 (2024).
Aeberli, I. et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care 36, 150–156 (2013).
Baena, M. et al. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues. Sci. Rep. 6, 26149 (2016).
Li, P. et al. A high-fructose diet impairs Akt and PKCzeta phosphorylation and GLUT4 translocation in rat skeletal muscle. Horm. Metab. Res. 40, 528–532 (2008).
Rai, A. K. et al. Fructose-induced AGEs-RAGE signaling in skeletal muscle contributes to impairment of glucose homeostasis. J. Nutr. Biochem. 71, 35–44 (2019).
Marek, G. et al. Adiponectin resistance and proinflammatory changes in the visceral adipose tissue induced by fructose consumption via ketohexokinase-dependent pathway. Diabetes 64, 508–518 (2015).
Andres-Hernando, A. et al. Deletion of fructokinase in the liver or in the intestine reveals differential effects on sugar-induced metabolic dysfunction. Cell Metab. 32, 117–127 (2020).
Seyssel, K. et al. Fructose overfeeding in first-degree relatives of type 2 diabetic patients impacts energy metabolism and mitochondrial functions in skeletal muscle. Mol. Nutr. Food Res. 60, 2691–2699 (2016).
Schwarz, J. M. et al. Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat. J. Clin. Endocrinol. Metab. 100, 2434–2442 (2015).
Agrawal, R. et al. Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity. J. Cereb. Blood Flow Metab. 36, 941–953 (2016).
Garcia-Arroyo, F. E. et al. Allopurinol prevents the lipogenic response induced by an acute oral fructose challenge in short-term fructose fed rats. Biomolecules 9, 601 (2019).
Choi, Y. J. et al. Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest. 94, 1114–1125 (2014).
Sanchez-Lozada, L. G. et al. Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J. Biol. Chem. 294, 4272–4281 (2019).
Cicerchi, C. et al. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB J. 28, 3339–3350 (2014).
Kang, D. H., Park, S. K., Lee, I. K. & Johnson, R. J. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J. Am. Soc. Nephrol. 16, 3553–3562 (2005).
Crescenzo, R. et al. Increased skeletal muscle mitochondrial efficiency in rats with fructose-induced alteration in glucose tolerance. Br. J. Nutr. 110, 1996–2003 (2013).
Garcia-Berumen, C. I. et al. The severity of rat liver injury by fructose and high fat depends on the degree of respiratory dysfunction and oxidative stress induced in mitochondria. Lipids Health Dis. 18, 78 (2019).
Cioffi, F. et al. Fructose-rich diet affects mitochondrial DNA damage and repair in rats. Nutrients 9, 323 (2017).
Hernandez-Rios, R. et al. Low fructose and low salt diets increase mitochondrial DNA in white blood cells of overweight subjects. Exp. Clin. Endocrinol. Diabetes 121, 535–538 (2013).
Wolf, J. P., Nguyen, N. U., Dumoulin, G. & Berthelay, S. Influence of hypertonic monosaccharide infusions on the release of plasma arginine vasopressin in normal humans. Horm. Metab. Res. 24, 379–383 (1992).
Andres-Hernando, A. et al. Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor. JCI Insight 6, e140848 (2021).
Kanbay, M. et al. The speed of ingestion of a sugary beverage has an effect on the acute metabolic response to fructose. Nutrients 13, 1916 (2021).
Enhorning, S. et al. Plasma copeptin, a unifying factor behind the metabolic syndrome. J. Clin. Endocrinol. Metab. 96, E1065–E1072 (2011).
Sigala, D. M. et al. Consuming sucrose- or HFCS-sweetened beverages increases hepatic lipid and decreases insulin sensitivity in adults. J. Clin. Endocrinol. Metab. 106, 3248–3264 (2021).
Jang, C. et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metab. 27, 351–361 (2018).
Ushijima, K., Riby, J. E., Fujisawa, T. & Kretchmer, N. Absorption of fructose by isolated small intestine of rats is via a specific saturable carrier in the absence of glucose and by the disaccharidase-related transport system in the presence of glucose. J. Nutr. 125, 2156–2164 (1995).
Roncal-Jimenez, C. A. et al. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism 60, 1259–1270 (2011).
Socha-Banasiak, A. et al. Intestinal fructose transporters GLUT5 and GLUT2 in children and adolescents with obesity and metabolic disorders. Adv. Med. Sci. 69, 349–355 (2024).
Sundborn, G. et al. Are liquid sugars different from solid sugar in their ability to cause metabolic syndrome? Obesity 27, 879–887 (2019).
Gonzalez, J. T. Are all sugars equal? Role of the food source in physiological responses to sugars with an emphasis on fruit and fruit juice. Eur. J. Nutr. 63, 1435–1451 (2024).
Jung, S. et al. Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis. Nat. Metab. 7, 1801–1818 (2025).
Francey, C. et al. The extra-splanchnic fructose escape after ingestion of a fructose-glucose drink: an exploratory study in healthy humans using a dual fructose isotope method. Clin. Nutr. ESPEN 29, 125–132 (2019).
Jones, N. et al. Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation. Nat. Commun. 12, 1209 (2021).
Song, Z. et al. Role of fructose and fructokinase in acute dehydration-induced vasopressin gene expression and secretion in mice. J. Neurophysiol. 117, 646–654 (2017).
Staltner, R. et al. Fructose intake enhances lipoteichoic acid-mediated immune response in monocytes of healthy humans. Redox Biol. 85, 103729 (2025).
Nakagawa, T. et al. Fructose might be a clue to the origin of preeclampsia insights from nature and evolution. Hypertens. Res. 46, 646–653 (2023).
Jones, A. R. & Connor, D. E. Fructose metabolism by mature boar spermatozoa. Reprod. Fertil. Dev. 12, 355–359 (2000).
Lanaspa, M. A. et al. High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism. Proc. Natl Acad. Sci. USA 115, 3138–3143 (2018).
Wang, M. et al. Elevated fructose and uric acid through aldose reductase contribute to experimental and human alcoholic liver disease. Hepatology 72, 1617–1637 (2020).
Mirtschink, P. & Krek, W. Hypoxia-driven glycolytic and fructolytic metabolic programs: pivotal to hypertrophic heart disease. Biochim. Biophys. Acta 1863, 1822–1828 (2016).
Kanbay, M. et al. Responses to hypoxia: how fructose metabolism and hypoxia-inducible factor-1a pathways converge in health and disease. Curr. Nutr. Rep. 12, 181–190 (2023).
Andres-Hernando, A. et al. Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nat. Commun. 8, 14181 (2017).
Mirtschink, P. et al. HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522, 444–449 (2015).
Shepherd, E. L. et al. Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis. JHEP Rep. 3, 100217 (2021).
Wang, S. et al. Acute heat stress upregulates Akr1b3 through Nrf-2 to increase endogenous fructose leading to kidney injury. J. Biol. Chem. 301, 108121 (2025).
van Zuylen, M. L. et al. Perioperative cerebrospinal fluid sorbitol and fructose concentrations in patients undergoing thoracic aortic surgery. Br. J. Anaesth. 129, e73–e76 (2022).
Hwang, J. J. et al. Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women. PLoS ONE 10, e0128582 (2015).
Lanaspa, M. A. et al. Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat. Commun. 4, 2434 (2013).
Andres-Hernando, A. et al. Identification of a common ketohexokinase-dependent link driving alcohol intake and alcohol-associated liver disease in mice. Nat. Metab. 7, 2250–2267 (2025).
Lanaspa, M. A. et al. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J. Am. Soc. Nephrol. 25, 2526–2538 (2014).
Roncal Jimenez, C. A. et al. Fructokinase activity mediates dehydration-induced renal injury. Kidney Int. 86, 294–302 (2014).
Park, T. J. et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356, 307–311 (2017).
Hwang, J. J. et al. The human brain produces fructose from glucose. JCI Insight 2, e90508 (2017).
Prockop, L. D. Hyperglycemia, polyol accumulation, and increased intracranial pressure. Arch. Neurol. 25, 126–140 (1971).
Regenold, W. T. et al. Relationship of cerebrospinal fluid glucose metabolites to MRI deep white matter hyperintensities and treatment resistance in bipolar disorder patients. Bipolar Disord. 10, 753–764 (2008).
Regenold, W. T., Phatak, P., Makley, M. J., Stone, R. D. & Kling, M. A. Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression. J. Neurol. Sci. 275, 106–112 (2008).
Smith, S. L., Novotny, M. & Karmen, A. Elevation of certain polyols in the cerebrospinal fluid of patients with multiple sclerosis. J. Chromatogr. 336, 351–355 (1984).
Tigchelaar, C. et al. Elevated cerebrospinal fluid glucose levels and diabetes mellitus are associated with activation of the neurotoxic polyol pathway. Diabetologia 65, 1098–1107 (2022).
Watanabe, S., Kamiyama, J., Chigasaki, H. & Yoshioka, S. Polyol content of cerebrospinal fluid in brain-tumor patients. J. Neurosurg. 70, 183–189 (1989).
Xu, J. et al. Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia. Sci. Rep. 6, 27524 (2016).
Zhao, Q. et al. AKR1B1-dependent fructose metabolism enhances malignancy of cancer cells. Cell Death Differ. 31, 1611–1624 (2024).
Aloia, J. F. Monosaccharides and polyols in diabetes mellitus and uremia. J. Lab. Clin. Med. 82, 809–817 (1973).
Daniels, L. J. et al. Elevated myocardial fructose and sorbitol levels are associated with diastolic dysfunction in diabetic patients, and cardiomyocyte lipid inclusions in vitro. Nutr. Diabetes 11, 8 (2021).
Heaf, D. J. & Galton, D. J. Sorbitol and other polyols in lens, adipose tissue and urine in diabetes mellitus. Clin. Chim. Acta 63, 41–47 (1975).
Nakatsuka, Y. et al. Hyperfructosemia in sleep disordered breathing: metabolome analysis of Nagahama study. Sci. Rep. 13, 12735 (2023).
Canovas, J. A., Wang, L., Mohamed, A. A. M., Abbott, L. F. & Zuker, C. S. A brain center that controls consummatory responses. Cell 118, 6907–6922.e17 (2025).
de Araujo, I. E. et al. Food reward in the absence of taste receptor signaling. Neuron 57, 930–941 (2008).
Andres-Hernando, A. et al. Sugar causes obesity and metabolic syndrome in mice independently of sweet taste. Am. J. Physiol. Endocrinol. Metab. 319, E276–E290 (2020).
Payant, M. A. & Chee, M. J. Neural mechanisms underlying the role of fructose in overfeeding. Neurosci. Biobehav. Rev. 128, 346–357 (2021).
Cha, S. H., Wolfgang, M., Tokutake, Y., Chohnan, S. & Lane, M. D. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc. Natl Acad. Sci. USA 105, 16871–16875 (2008).
Luo, S., Monterosso, J. R., Sarpelleh, K. & Page, K. A. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. Proc. Natl Acad. Sci. USA 112, 6509–6514 (2015).
Purnell, J. Q. et al. Brain functional magnetic resonance imaging response to glucose and fructose infusions in humans. Diabetes Obes. Metab. 13, 229–234 (2011).
Johnson, R. J., Wilson, W. L., Bland, S. T. & Lanaspa, M. A. Fructose and uric acid as drivers of a hyperactive foraging response: a clue to behavioral disorders associated with impulsivity or mania? Evol. Hum. Behav. 42, 194–203 (2021).
Johnson, R. J. et al. Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism? Am. J. Clin. Nutr. 117, 455–466 (2023).
Friedman, M. I., Harris, R. B., Ji, H., Ramirez, I. & Tordoff, M. G. Fatty acid oxidation affects food intake by altering hepatic energy status. Am. J. Physiol. 276, R1046–R1053 (1999).
Ishimoto, T. et al. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc. Natl Acad. Sci. USA 109, 4320–4325 (2012).
Shapiro, A. et al. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1370–R1375 (2008).
Shapiro, A., Tumer, N., Gao, Y., Cheng, K. Y. & Scarpace, P. J. Prevention and reversal of diet-induced leptin resistance with a sugar-free diet despite high fat content. Br. J. Nutr. 106, 390–397 (2011).
Dushay, J. R. et al. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol. Metab. 4, 51–57 (2015).
Togo, J., Hu, S., Li, M., Niu, C. & Speakman, J. R. Impact of dietary sucrose on adiposity and glucose homeostasis in C57BL/6J mice depends on mode of ingestion: liquid or solid. Mol. Metab. 27, 22–32 (2019).
Miller, C. O. et al. Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects. Am. J. Physiol. Endocrinol. Metab. 315, E386–E393 (2018).
Hallfrisch, J. et al. Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. J. Nutr. 113, 1819–1826 (1983).
Smajis, S. et al. Metabolic effects of a prolonged, very-high-dose dietary fructose challenge in healthy subjects. Am. J. Clin. Nutr. 111, 369–377 (2020).
Perez-Pozo, S. E. et al. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int. J. Obes. 34, 454–461 (2010).
Cox, C. L. et al. Circulating concentrations of monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and soluble leukocyte adhesion molecule-1 in overweight/obese men and women consuming fructose- or glucose-sweetened beverages for 10 weeks. J. Clin. Endocrinol. Metab. 96, E2034–E2038 (2011).
Reungjui, S. et al. Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia. Kidney Int. 72, 1483–1492 (2007).
Sievenpiper, J. L. et al. Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis. Ann. Intern. Med. 156, 291–304 (2012).
Sullivan, J. S. et al. Oral fructose absorption in obese children with non-alcoholic fatty liver disease. Pediatr. Obes. 10, 188–195 (2015).
Nakagawa, T. et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am. J. Physiol. Renal Physiol. 290, F625–F631 (2006).
Reungjui, S. et al. Thiazide diuretics exacerbate fructose-induced metabolic syndrome. J. Am. Soc. Nephrol. 18, 2724–2731 (2007).
Erkin-Cakmak, A. et al. Isocaloric fructose restriction reduces serum d-lactate concentration in children with obesity and metabolic syndrome. J. Clin. Endocrinol. Metab. 104, 3003–3011 (2019).
Jensen, T. et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J. Hepatol. 68, 1063–1075 (2018).
Ouyang, X. et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J. Hepatol. 48, 993–999 (2008).
Maersk, M. et al. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am. J. Clin. Nutr. 95, 283–289 (2012).
Schwimmer, J. B. et al. Effect of a low free sugar diet vs usual diet on nonalcoholic fatty liver disease in adolescent boys: a randomized clinical trial. JAMA 321, 256–265 (2019).
Schwarz, J. M. et al. Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology 153, 743–752 (2017).
Ishimoto, T. et al. High-fat and high-sucrose (Western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology 58, 1632–1643 (2013).
Wang, M. et al. Elevated fructose and uric acid via aldose reductase contribute to experimental and human alcoholic liver disease. Hepatology 72, 1617–1637 (2020).
Shi, C. et al. Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines. Mol. Med. Rep. 16, 2767–2772 (2017).
Singh, A. K. et al. Fructose-induced hypertension: essential role of chloride and fructose absorbing transporters PAT1 and Glut5. Kidney Int. 74, 438–447 (2008).
Zhang, R. et al. Abnormal activation of the mineralocorticoid receptor in the aldosterone-sensitive distal nephron contributes to fructose-induced salt-sensitive hypertension. Preprint at bioRxiv https://doi.org/10.1101/2024.08.19.608663 (2024).
Sanchez-Lozada, L. G. et al. Sugar, salt, immunity and the cause of primary hypertension. Clin. Kidney J. 16, 1239–1248 (2023).
Cirillo, P. et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J. Am. Soc. Nephrol. 20, 545–553 (2009).
Lodge, M. et al. Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells. Sci. Rep. 14, 4020 (2024).
Johnson, R. J. et al. Do thrifty genes exist? Revisiting uricase. Obesity 30, 1917–1926 (2022).
Roncal-Jimenez, C. A. et al. Aging-associated renal disease in mice is fructokinase dependent. Am. J. Physiol. Renal Physiol. 311, F722–F730 (2016).
Chen, W. L. et al. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. JCI Insight 5, e131596 (2020).
Carreno, D. V. et al. Dietary fructose promotes prostate cancer growth. Cancer Res. 81, 2824–2832 (2021).
Liu, H. et al. Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. 70, 6368–6376 (2010).
Kang, Y. L. et al. The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer. Exp. Mol. Med. 56, 220–234 (2024).
Kim, J. et al. Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer. Nat. Commun. 11, 5436 (2020).
Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345–1349 (2019).
Bu, P. et al. Aldolase B-mediated fructose metabolism drives metabolic reprogramming of colon cancer liver metastasis. Cell Metab. 27, 1249–1262 (2018).
Xu, D. et al. The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62. Sci. Adv. 5, eaav4570 (2019).
Tee, S. S. et al. Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging. Sci. Adv. 8, eabm7985 (2022).
Jeong, S. et al. High fructose drives the serine synthesis pathway in acute myeloid leukemic cells. Cell Metab. 33, 145–159 (2021).
Yan, H. et al. Hexokinase 2 senses fructose in tumor-associated macrophages to promote colorectal cancer growth. Cell Metab. 36, 2449–2467 (2024).
Schild, T. et al. Metabolic engineering to facilitate anti-tumor immunity. Cancer Cell 43, 552–562 (2025).
Page, K. A. et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA 309, 63–70 (2013).
Regenold, W. T., Phatak, P., Kling, M. A. & Hauser, P. Post-mortem evidence from human brain tissue of disturbed glucose metabolism in mood and psychotic disorders. Mol. Psychiatry 9, 731–733 (2004).
Wang, Z. et al. Early life high fructose impairs microglial phagocytosis and neurodevelopment. Nature 644, 759–768 (2025).
Cisternas, P. et al. Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance. Biochim. Biophys. Acta 1852, 2379–2390 (2015).
Mohamed, H. E., Asker, M. E., Shaheen, M. A., Eissa, R. G. & Younis, N. N. Alleviation of fructose-induced Alzheimer’s disease in rats by pioglitazone and decaffeinated green coffee bean extract. J. Food Biochem. 45, e13715 (2021).
Mohamed, H. E., Asker, M. E., Younis, N. N., Shaheen, M. A. & Eissa, R. G. Modulation of brain insulin signaling in Alzheimer’s disease: new insight on the protective role of green coffee bean extract. Nutr. Neurosci. 23, 27–36 (2020).
Steinmann, B., Gitzelmann, R. & Van den Berghe, G. in The Metabolic and Molecular Basis of Inherited Disease (eds Scriver C. et al.) 1489–1520 (McGraw-Hill, 2001).
Lanaspa, M. A. et al. Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J. Clin. Invest. 128, 2226–2238 (2018).
Andres-Hernando, A. et al. Endogenous fructose production and metabolism drive metabolic dysregulation and liver disease in mice with hereditary fructose intolerance. Nutrients 15, 4376 (2023).
Koene, E. J. et al. Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance. J. Clin. Invest. 135, e187376 (2025).
Cleave, T. L. & Campbell, G. D. The saccharine disease. Am. J. Proctol. 18, 202–210 (1967).
US Department of Health and Human Services. Centers for Disease Control and Prevention. After 20-year increase, new diabetes cases decline. CDC Archive https://archive.cdc.gov/www_cdc_gov/diabetes/research/reports/cdc-research-20yr-report.html (2018).
Rader, B., Hazan, R. & Brownstein, J. S. Changes in adult obesity trends in the US. JAMA Health Forum 5, e243685 (2024).
Korsmo, H. W., Ekperikpe, U. S. & Daehn, I. S. Emerging roles of xanthine oxidoreductase in chronic kidney disease. Antioxidants 13, 712 (2024).
Saxena, A. R. et al. A phase 2a, randomized, double-blind, placebo-controlled, three-arm, parallel-group study to assess the efficacy, safety, tolerability and pharmacodynamics of PF-06835919 in patients with non-alcoholic fatty liver disease and type 2 diabetes. Diabetes Obes. Metab. 25, 992–1001 (2023).
Park, S. H. et al. Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism. JCI Insight 9, e184396 (2024).
Johnson, R. J. et al. Water scarcity and conservation and their role in obesity in nature and in humans. J. Intern. Med. 298, 562–577 (2025).
Perheentupa, J. & Raivio, K. Fructose-induced hyperuricaemia. Lancet 2, 528–531 (1967).
Brown, C. M., Dulloo, A. G., Yepuri, G. & Montani, J. P. Fructose ingestion acutely elevates blood pressure in healthy young humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R730–R737 (2008).
Sanchez-Lozada, L. G. et al. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats. Am. J. Physiol. Renal Physiol. 292, F423–F429 (2007).


